Cardiotoxicity studies with diazoxide, reserpine, guanethidine, and combinations of diazoxide and propranolol in dogs.
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Animals↗
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Hyperglycemic, antihypertensive and antidiuretic properties of Go. 8288 and its comparison with diazoxide.
Hyperglycemic, antihypertensive and antidiuretic activities of Go.8288 and diazoxide were evaluated in the rat. Go.8288 and diazoxide induced hyperglycemia which was blocked by adrenalectomy and demedullation. Pretreatmnet with hydrocortisone completely restored the hyperglycemic effect of diazoxide but only partially that of Go.8288. The hyperglycemic effect of Go.8288 and diazoxide was antagonized by glibenclamide, whereas tolbutamide antagonized only diazoxide-induced hyperglycemia. Pretreatment with oxprenolol antagonized diazoxide-induced hyperglycemia but not that of Go.8288. Guanethidine antagonized the hyperglycemic effect of Go.8288 but not that of diazoxide. Go.8288 and diazoxide markedly inhibited insulin secretion in vivo. Unlike Go.8288, diazoxide further accentuated the hyperglycemic effect in the streptozotocin diabetic rat. Diazoxide significantly increased plasma FFA and plasma renin activity but Go.8288 had no effect. In the normotensive cats and dogs and renal hypertensive rats both compounds lowered arterial blood pressure. Unlike diazoxide, Go.8288 was active orally in normotensive dogs. Similar to diazoxide Go.8288 showed an antidiuretic effect in the rat. It is therefore concluded that despite some similarities, Go.8288 shows important differences in its biological profile from that of diazoxide.
Amidines↗
Dose-response relation of diazoxide in children with hypertension.
Diazoxide was administered to sixteen pediatric patients (ages 10 months to 13 years) with secondary forms of hypertension. Admission BP was 178+/-8/130+/-5 mm Hg (mean +/- SEM). Diazoxide was administered rapidly intravenously in doses ranging from 2 to 7.5 mg/kg. A significant (P less than 0.001), linear log dose-response relation was obtained which showed that a 3 mg/kg dose of diazoxide lowered diastolic BP by an average of 30 mm Hg. In five patients reduction of idastolic BP by a single injection of diazoxide was no different than when the same total dose was given as two or three small injections repeated at fifteen to twenty minute intervals. It is concluded that 1) many hypertensive children respons significantly to doses of diazoxide smaller than the usually recommended 5 mg/kg; 2) diazoxide has a significant dose-response relation in hypertensive pediatric patients; and 3) the desired blood pressure response in hypertensive children can be titrated using repeated small injections of diazoxide.
Adolescent↗
Inhibition of glucagon secretion by diazoxide in vitro.
UNLABELLED: The effect of diazoxide on the secretion of glucagon and insulin was studied using the isolated perfused rat pancreas. The perfusate concentration of D-glucose was kept constant at 5.6 mM. Five secretagogues of both glucagon and insulin--10 mM L-arginine, 5 mM L-leucine, 1.4 muM prostaglandin F2alpha, 100 nM bovine growth hormone, and 10 nM theophylline--were administered individually in the presence or absence of 325 muM diazoxide. Basal secretion of glucagon or insulin was not discernibly affected by diazoxide. With diazoxide the secretion of glucagon was (a) abolished completely in response to L-arginine or L-leucine; (b) inhibited partially in response to prostaglandin F2alpha; (c) unaltered in response to growth hormone; and (d) unchanged or, at times, enhanced in response to theophylline. On the other hand, the secretion of insulin induced by each of these agents was inhibited effectively by diazoxide. CONCLUSIONS: (a) Diazoxide inhibits the secretion of glucagon as well as insulin in response to certain secretagogues independent of any changes in prevailing levels of glucose. (b) At the concentration tested, diazoxide is a more potent and consistent inhibitor of the release of insulin than of glucagon.
Animals↗
Decreased plasma protein binding of diazoxide in uremia.
The effect of uremia on the binding of diazoxide to plasma proteins was studied. An equilibrium dialysis technique, using diazoxide-minus14C at approximately 30 and 300 mug/ml in the plasma phase, was used to measure diazoxide binding to plasma. Serum albumin concentration (Alb) and serum creatinine (Cr) or blood urea nitrogen (BUN) were negatively correlated. By single regression analysis, per cent free diazoxide (%FD) correlated negatively with Alb and positively with Cr or BUN. When %FD was regressed simultaneously against Alb and Cr or BUN, Alb emerged as the sole determinant of %FD (p less than 0.001), indicating that creatinine or BUN correlated with %FD by their inverse correlation to Alb rather than by an effect on drug protein binding. At the levels of Alb studied, %FD varied over a 2-fold range. In a retrospective study of the influence of uremia on diazoxide effect in hypertensive patients, a relatively low correlation (r, 0.59) was found between BUN and hypotensive effect. Prospective studies involving correlations of drug effect with renal function and %FD are required to assess the clinical importance of decreased binding of diazoxide to uremic plasma.
Adult↗
Effect of diazoxide on left ventricular performance in hypertension.
The effect of diazoxide on left ventricular performance during rest and isometric exercise (handgrip) was examined in 16 unselected hypertensive patients, 6 of whom had been pretreated with the beta-adrenergic blocking agent pindolol. Diazoxide regularly and promptly produced a fall in left ventricle systolic and end diastolic pressures, and an increase in heart rate and left ventricular dp/dtmax. Haemodynamic changes were maximal 2 minutes after injection of the drug and decreased little over the next 8 minutes. After beta-adrenergic blockade, diazoxide caused a more pronounced reduction in left ventricular systolic pressure and a less marked fall in end-diastolic pressure, whilst the diazoxide-induced rise in heart rate was partially and the increase of dp/dtmax was completly inhibited. The increase in systolic pressure during isometric exercise was not influenced by diazoxide, but the positive inotropic reaction was augmented. The findings appear to show that cardiac stimulation by diazoxide is due to a reflex mechanism transmitted by baroreceptors, and that improvement of cardiac performance is mainly due to a reduction of left ventricular after-load.
Adult↗
Mechanical and ionic response of rat aorta to diazoxide.
Diazoxide provoked concentration-dependent and endothelium-independent relaxations of the mechanical responses evoked by low concentrations of KCl. Glibenclamide, tolbutamide and tetraethylammonium shifted the concentration-response curve for diazoxide to the right. The drug also caused a dose-dependent stimulation of 86Rb outflow which was inhibited by glibenclamide and tolbutamide. Diazoxide (10(-4) and 10(-3) M) inhibited the contractions elicited by 10(-1) M K+ and provoked a concentration-dependent reduction in the contractile responses to Ca2+. Diazoxide also reduced the KCl (8 x 10(-2) M)-induced increase in 45Ca outflow. These data indicate that the vasorelaxant properties of diazoxide are probably related to an inhibition of Ca2+ entry into smooth muscle cells. The reduction in Ca2+ entry appears to result from K+ channel activation. At high concentrations, diazoxide also exhibited antagonistic actions on voltage-sensitive Ca2+ channels.
Animals↗
Use of diphenylhydantoin and diazoxide to investigate insulin secretory mechanisms.
In the isolated, perfused rat pancreas, we contrasted effects of diphenylhydantoin (DPH) and diazoxide on glucose-induced biphasic insulin secretion. Either drug partially inhibited the first phase. However, DPH completely inhibited the second phase, whereas diazoxide produced inhibition, then escape and post-inhibitory overshoot. Exposure to DPH prior to glucose further inhibited the first phase, and increasing the dose had no additional effects, whereas only raising the diazoxide dose intensified inhibition of early release. DPH sequentially suppressed early response to a series of two, short, glucose pulses. In contrast, no additional effects of diazoxide were noted after its initial inhibition of the first pulse. A computer analysis was programmed from hypotheses based on these experiments. It suggests that DPH inhibits release from a labile compartment and provision of insulin to that compartment, whereas diazoxide divides the labile compartment into two sequential subcompartments. Further, the computer analysis indicates that, with diazoxide, insulin (or substances on which secretion depends) accumulates not at the final release step but at a proximal portion of the labile compartment.
Animals↗
On the mechanism of diazoxide-induced hyperglycemia.
Infusion of diazoxide (16.5 mg./kg. in 10 minutes) into normal unanesthetized dogs resulted in a prompt hyperglycemia due to increased hepatic glucose production as measured with a 3-3H-glucose primer-infusion technique. Plasma insulin and glucagon were decreased. Glucose uptake failed to increase. Diazoxide administration during period of alpha adrenergic receptor blockade with phentolamine still caused hyperglycemia and increased glucose production. Glucose uptake was inhibited despite adequate plasma insulin. Infusion of somatostatin along with insulin prevented the effects of diazoxide on plasma glucose and glucose production. It is concluded that diazoxide hyperglycemia is not due solely to decreased insulin secretion or increased epinephrine secretion and that glucagon is not a contributory factor. Diazoxide may act directly to increase glucose production and inhibit glucose uptake. Somatostatin appears capable of blocking the effect of diazoxide on glucose production by an unknown mechanism.
Animals↗
Evidence for the involvement of alpha-adrenoceptor blockade in the antihypertensive action of diazoxide in the renal hypertensive rat.
The effects of diazoxide on the blood pressure and heart rate of conscious renal hypertensive rats have been investigated. The antihypertensive action of diazoxide has been studied in relation to the effects of diazoxide pretreatment on pressor responses to stimulation of the complete sympathetic outflow and to injections of noradrenaline, phenylephrine, angiotensin and serotonin in pithed rats. In pithed preparations, pressor responses to sympathetic nerve stimulation, and to injected noradrenaline and phenylephrine were significantly reduced by diazoxide pretreatment, at a time corresponding to maximal reduction of blood pressure in conscious animals. At this time there was no significant reduction of pressor responses to injected angiotensin or serotonin. These findings suggest a contribution of alpha-adrenoceptor blockade to the antihypertensive activity of diazoxide.
Adrenergic alpha-Antagonists↗
Drug interaction: diazoxide and diphenylhydantoin.
In two children treated for hypoglycemia and convulsions with diazoxide and diphenylhydantoin, therapeutic serum diphenylhydantoin levels were not achieved despite doses of diphenylhydantoin of 17 and 29 mg/kg/day, respectively. After diazoxide was discontinued, serum diphenylhydantoin levels were within the therapeutic range in each patient with doses of 6.6 and 10 mg/kg/day, respectively. Serum diphenylhydantoin fell to undetectable levels within four days after experimental reinitiation of diazoxide administration in one patient. Although the mechanism for the effect of diazoxide on serum concentrations of diphenylhydantoin is uncertain, an increased rate of metabolism of diphenylhydantoin is suggested by our findings. Decreased plasma protein binding of diphenylhydantoin, induced by diazoxide, was observed and may play a role.
Administration, Oral↗
Trial of the prophylactic effect of diazoxide in the treatment of familial periodic hypokalemia.
Five patients suffering from familial periodic paralysis with hypokalemia (FPP) were exposed to standard paralysis induction trials which elicited total paralyysis and hypokalemia. In all cases the serum potassium fell to or below 2.6 mmol/1. After being pre-treated with diazoxide for 72 h, the same five patients were exposed to the same standardized paralysis induction procedure. None of them developed any demonstrable symptoms or signs of paralysis. In one the serum potassium dropped to 3.2 mmol/1, but in all the others the levels were higher. The serum glucose level was significant higher (P less than 0.01), the serum insulin level was significant lower (P less than 0.01) when induction of paralysis was attempted under diazoxide cover than during the untreated stimulation phase. Three patients were put on prophylactic diazoxide medication. After a few months, without paralytic episodes or other prophylactic drugs, adaptation to the diazoxide occurred and the previous, frequent paralytic episodes returned in unchanged severity. This experimental prophylactic effect of diazoxide supports the hypothesis that the glucose deposition in muscles is a major step in eliciting the parese attacks in FPP.
Acute Disease↗
Mechanical and metabolic effects of diazoxide in rat uterus.
Diazoxide relaxed both polarized and depolarized rat uterus. The drug also conteracted the contractions elicited by Ca2+ in a competitive manner. The relaxing effect was associated with an increase in the tissue level of cyclic AMP. This metabolic effect of diazoxide was inhibited by propranolol-treatment and in preparations from reserpinized animals, while the mechanical effects were only partially reduced. Diazoxide was also found to increase the release of tritium from preparations preloaded with [3H]-noradrenaline. It is suggested that diazoxide may induce some of its mechanical and metabolic effects by releasing the adrenergic transmittor substance noradrenaline. An effect of diazoxide on the Ca2+-metabolism is also probable.
Animals↗
Intravenous diazoxide in treatment of hypertension associated with recent myocardial infarction.
Twenty patients with blood pressure over 180/110 mm Hg one hour after admission to a coronary care unit with recent acute myocardial infarction were given intravenous diazoxide in a bolus of 300 mg. The average blood pressure before diazoxide was 194/122 mm Hg. Blood pressure fell considerably in all patients, though six patients required two injections. The average fall was 58 mm Hg systolic and 40 mm Hg diastolic. No patient became severely hypotensive. The heart rate increased by an average of 10 beats/min. In nine patients the electrocardiographic changes immediately after the administration of diazoxide suggested an increase in myocardial injury. Though none of the patients seemed to deteriorate clinically from the diazoxide the electrocardiographic changes suggested that the use of intravenous diazoxide to lower blood pressure in patients with acute myocardial infarction might possibly be deleterious.
Acute Disease↗
Safety of intravenous diazoxide in children with severe hypertension.
The safety and efficacy of diazoxide administered intravenously in the treatment of children with acute severe hypertension have been evaluated by a collaborative study. Observations of the response of blood pressure in 36 patients, ranging in age from two months to 18 years, during the initial episode of hospitalization reveal diazoxide treatment to be effective in lowering blood pressure in 94 per cent of the cases. No serious adverse circulatory, fluid and electrolyte, metabolic or hematologic effects were observed. Symptomatic and subjective reactions observed with diazoxide administered intravenously to children were identical with those described in adults. Reinstitution of other means of antihypertensive therapy is safe and effective when delayed until the transiently induced period of hypotension has passed. Repeated use of diazoxide for subsequent recurrence of severe hypertension was equally effective and safe in 93 per cent of the instances. The results lead us to recommend the use of intravenous diazoxide for treatment of children with severe symptomatic hypertension especially when it is refractory to control by other hypertensive agents.
Adolescent↗
Pharmacokinetics and response to diazoxide in renal failure.
Diazoxide is given by rapid intravenous injection for the urgent reduction of high blood pressure in patients with all grades of renal function. Oral diazoxide produces less consistent effects. Protein binding of diazoxide is reduced in renal failure and this can be related to reduction of albumin concentration. There is a relation between impairment of renal function and the hypotensive effect of rapidly injected diazoxide. This is explicable in terms of the greater concentration of free (unbound) drug achieved after rapid injection in patients with renal failure. Renal clearance of diazoxide and its metabolites is impaired in renal failure but this is unlikely to affect its activity.
Administration, Oral↗
Palliative treatment of hyperinsulinism with cyproheptadine and diazoxide.
Treatment for hyperinsulinism in infants and children can be difficult and has included numerous treatment modalities. This paper reports 16 months of palliative treatment with cyproheptadine and diazoxide in a child with hyperinsulinism initially diagnosed at 6 months of age (her insulin level was 80 microU/mL while her glucose level was 38 mg/dL). She continued to have episodes of staring and alteration in level of consciousness while receiving her usual doses of diazoxide (12 mg/kg) alone. Mean nocturnal glucose values, which were quite low during treatment with diazoxide alone, improved significantly with the addition of cyproheptadine to her therapeutic regimen. Fasted C-peptide values, elevated during diazoxide alone, returned to the normal range with combination treatment for 16 months. Cyproheptadine and diazoxide in combination may be useful for treatment of hyperinsulinism that presents after the neonatal period.
Blood Glucose↗
Nonemergency use of slow infusions of diazoxide.
Slow infusions of diazoxide were administered to 10 hypertensive patients who had stable, nonaccelerated hypertension. The 10-min diazoxide infusion was associated with a 16% average reduction in arterial pressure, a 21% average increase in heart rate, a 16% average increase in cardiac output, and a 36% reduction in total peripheral resistance. These changes in hemodynamic parameters lasted for an average of 70 min. It was concluded that slow infusions of diazoxide produce a consistent and predictable antihypertensive effect in patients with stable, nonaccelerated hypertension. Slow infusions of diazoxide may have a limited use in nonemergency situations where an abrupt change in arterial pressure is to be avoided and a parenteral antihypertensive agent is needed.
Adult↗